FDA Clears Peptide-Drug Conjugate for RRMM

The FDA Friday approved the first anticancer peptide-drug conjugate, melphalan flufenamide, or melflufen, for use in combination with dexamethasone in adult patients with relapsed/refractory multiple myeloma (RRMM), who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody.

The product, created by Swedish biotech firm Oncopeptides AB, was granted accelerated approval based on the phase 2 HORIZON study. The doublet was found to elicit an overall response rate (ORR) of 23.7% in heavily pretreated patients with RRMM; the median duration of response (DOR) in these patients was 4.2 months. The combination also showed activity in a subset of patients who had extramedullary disease (41%).

In the trial, investigators enrolled a total of 157 patients with RRMM who had received 2 or more prior lines of therapy, were exposed to an immunomodulatory drug and a proteasome inhibitor, and were refractory to pomalidomide (Pomalyst) and/or daratumumab (Darzalex).

Participants had triple-class refractory disease and/or EMD and/or high-risk cytogenetic features. To be eligible for enrollment, patients had to have had an ECOG performance status of 0 to 2; 97 of those enrolled had triple-class refractory disease and had received at least 4 previous lines of treatment.

Study participants were given 40 mg of melphalan flufenamide on day 1 plus 40 mg of dexamethasone on days 1, 8, and 15. However, patients who were 75 years of age or older were given 20 mg of dexamethasone instead. Treatment was administered in 28-day cycles until either progressive disease or unacceptable toxicity.

The primary end point of the trial was ORR, while secondary end points included clinical benefit rate, progression-free survival (PFS), overall survival (OS), DOR, time to response, time to progression, time to next treatment, safety, and health-related quality of life.

Data from the trial presented during the 2020 European Hematology Association Annual Meeting showed that among participants who experienced responses with the combination, the median PFS was 8.5 months (95% CI, 5.4-13.4) in the intent-to-treat population, whereas it was 8.5 months (95% CI, 5.3-13.4) and 17.3 months (95% CI, 5.3–not evaluable) in those with triple-class refractory disease and those with EMD, respectively.

Additionally, the median OS in the ITT population was 11.6 months (95% CI, 9.3-15.4) vs 11.2 months (95% CI, 7.7-13.2) and 6.5 months (95% CI, 5.1-9.7) in the triple-class refractory and EMD subgroups, respectively.

The most frequently reported grade 3 or 4 toxicities with the doublet included neutropenia (79%), thrombocytopenia (76%), and anemia (43%). The most commonly experienced non-hematologic toxicity that was grade 3 or 4 in severity was pneumonia (10%).

The peptide-drug conjugate rapidly delivers an alkylating payload into tumor cells, according to the company.

“The accelerated approval of [melphalan flufenamide] in the United States is an important milestone for Oncopeptides, and a major step ahead in fulfilling our mission, to bring hope to patients with difficult-to-treat hematological diseases, through innovative science," Marty J. Duvall, chief executive officer at Oncopeptides AB, said in a statement.